DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 11.14.2025 has been entered.
Status of the Claims
Claims 1-3, 5, 7, 10-16, and 29 are pending.
Claims 1 and 10 are newly amended.
Claim 29 is newly added.
Claims 1-3, 5, 7, 10-16, and 29 have been examined on their merits.
Withdrawn Objections & Rejections
The objections and rejections presented herein represent the full set of objections and rejections currently pending in the application. Any objections or rejections not specifically reiterated are hereby withdrawn.
The rejection of claims 1-3, 5, and 13-16 under 35 U.S.C. 103 as being unpatentable over Lim et al. (US 20160220613 A1, on IDS 11/04/2020, previously cited) in view of Lai et al. (Scientific Reports, 2017, on IDS 07/05/2022, previously cited) and Mathieu et al. (Cell Stem Cell, 2015, previously cited) is withdrawn in order to address the claims amendments.
The rejection of claim 7 under 35 U.S.C. 103 as being unpatentable over Lim et al. (US 20160220613 A1, on IDS 11/04/2020, previously cited) in view of Lai et al. (Scientific Reports, 2017, on IDS 07/05/2022, previously cited) and Mathieu et al. (Cell Stem Cell, 2015, previously cited), as applied to claim 1 and further in view of Collas et al. (Reproductive BioMedicine Online, 2006, previously cited) is withdrawn in order to address the claims amendments.
The rejection of claim 10 under 35 U.S.C. 103 as being unpatentable over Lim et al. (US 20160220613 A1, on IDS 11/04/2020, previously cited) in view of Lai et al. (Scientific Reports, 2017, on IDS 07/05/2022, previously cited) and Mathieu et al. (Cell Stem Cell, 2015, previously cited), as applied to claim 1, and further in view of Anokye-Danso et al. (Cell Stem Cell, 2011, previously cited) is withdrawn in order to address the claims amendments.
The rejection of claims 11-12 under 35 U.S.C. 103 as being unpatentable over Lim et al. (US 20160220613 A1, on IDS 11/04/2020, previously cited) in view of Lai et al. (Scientific Reports, 2017, on IDS 07/05/2022, previously cited) and Mathieu et al. (Cell Stem Cell, 2015, previously cited), as applied to claim 1 above, and further in view of Jung et al. (ACS Chemical Biology, 2014, previously cited) is withdrawn in order to address the claims amendments.
Claim Interpretation
Claim 1 is limited to “de-differentiated fibroblasts.” While the specification states, “In some embodiments, passaged cells are defined as ‘dedifferentiated’ if expression of OCT-4 is detected” (paragraph [0116]), the disclosure does not specifically define what a de-differentiated fibroblast is.
As evidenced by Merriam-Webster (retrieved from internet 10/23/2024, previously cited), “dedifferentiation” means “reversion of a specialized structure (such as cells) to a more generalized or primitive conditions often as a preliminary physiological or structural change”.
Therefore, giving the term its broadest reasonable interpretation in view of the disclosure and the art, “de-differentiated fibroblasts” have been interpreted as any fibroblast-derived cell that has reverted to a more generalized or primitive condition, including any fibroblast-derived cell that expresses OCT-4.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 7 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 7 recites the limitation “the stem cells are pluripotent stem cells”. There is insufficient antecedent basis for this limitation in the claim.
It is noted that claim 1 previously recited a step of exposing fibroblasts to stem cells in order to dedifferentiate those cells. Since the claim no longer requires this step, the stem cells in claim 7 have broadly interpreted as any stem cell for any purpose.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-3, 5, 10, and 13-16 are rejected under 35 U.S.C. 103 as being unpatentable over Lim et al. (US 20160220613 A1, on IDS 11/04/2020, previously cited) in view of Lai et al. (Scientific Reports, 2017, on IDS 07/05/2022, previously cited), Mathieu et al. (Cell Stem Cell, 2015, previously cited) and Anokye-Danso et al. (Cell Stem Cell, 2011, previously cited).
In regards to claims 1-2, 5, 10, 13-14, Lim teaches a method for repairing cell homeostasis or treating an individual suffering from a disease or tissue injury with exosomes derived from MSCs (claims 10 and 12) that can specifically be used to treat intervertebral disc degeneration (paragraph [0077]). Lim teaches that the exosomes may be contained within a composition that may be conditioned media that may be used as a therapy (paragraphs [0173-0177, and 0282]).
In regards to a “de-differentiated fibroblast”, while, as taught by Lai, MSCs express OCT-4 (p7, third paragraph), Lim does not explicitly teach that the MSCs derived from fibroblasts specifically.
However, methods for “de-differentiating” MSCs from fibroblasts are known in the art.
In particular, Lai teaches a method for the efficient generation of induced Oct-4 expressing MSCs from human dermal fibroblasts, which is achieved by adding a cocktail of chemical inhibitors in culture without reprogramming media comprising transcription factors (Title, Abstract, p1; Discussion, p4; Figure 1, p3). Lai also teaches that MSCs are used in hundreds of clinical trials for disease treatments; have much higher clonogenicity compared to fibroblasts; can be passaged multiple times; and can be further differentiated into osteoblasts, adipocytes, and chondrocytes (Abstract, p1).
A person of ordinary skill in the arts would have been motivated to use de-differentiated fibroblasts because it could provide an alternate source of MSCs for when obtaining them from blood is not possible or practical, and do so in a way that would be less invasive for patients. Furthermore, because Lai teaches explicit for de-differentiating cells (MSCs) from fibroblasts without reprogramming media comprising transcription factors (Discussion, p4; Generation of iMSCs, p9); advocates for their use in therapeutic application (p9, last paragraph of Discussion); and Lim and Lai are in the same technical field of deriving MSCs for clinical application, it could have been done with predictable results and a reasonable expectation of success.
Lim as modified by Lai is silent as to the oxygen conditions of the de-differentiating cells.
However, a person of ordinary skill in the arts would have been motivated to de-differentiate fibroblasts in hypoxic conditions because Mathieu teaches that pluripotent stem cells (OCT-4 expressing cells) have distinct metabolic requirements, and reprogramming cells to pluripotency requires a shift from oxidative to glycolytic metabolism (Summary, p592). Moreover, in particular, Mathieu teaches that reprogramming is significantly more efficient under hypoxic (2% and 5%, which lies within the ranges as in claim 13) conditions (Reprogramming process has hypoxic expression signature, p593). Furthermore, because Mathieu teaches methods for reprogramming fibroblasts under hypoxic (2% and 5%) conditions (Reprogramming process has hypoxic expression signature, p593; Cell culture and reprogramming, p602); and Lim, Lai, and Mathieu are in the same technical field of utilizing OCT-4 positive cells, it could have been done with predictable results and a reasonable expectation of success.
Lim as modified by Lau and Mathieu does not explicitly teach a step of de-differentiating fibroblasts by exposure to valproic acid (VPA).
However, a person of ordinary skill in the arts would have been motivated to de-differentiate fibroblasts with VPA because Anokye-Danso teaches that VPA is required for reprogramming fibroblasts by specifically degrading Hdac2 which allows for highly efficient reprogramming without expression of other known reprogramming factors (Introduction, p376). Furthermore, because Anokye-Danso teaches method for reprogramming fibroblasts with VPA (Figure 1, p377), and Lai, Lim, Mathieu, and Anokye-Danso are in the same technical field of utilizing OCT-4 positive cells, it could have been done with predictable results and a reasonable expectation of success.
In regards to claim 3, Lim teaches that the exosomes express at least markers CD9 and CD63 (paragraph [0181]).
In regards to claim 15, Lim teaches that the exosomes may be purified by ion (of which an anion is a type) exchange chromatography (paragraph [0284]).
In regards to claim 16, Lim teaches that mesenchymal stem cells may be administered to an individual (paragraph [0331]). Lim also teaches that the use of bone marrow to treat disease is known in the art (paragraph [0106]). Therefore, a person of ordinary skill in the arts would have been motivated to use BM-MSCs because they are common in the art, and because Lim teaches both that MSCs and bone marrow can be administered to patients, it could have been done with predictable results and a reasonable expectation of success.
Therefore, the combined teachings of Lim, Lai, Mathieu, and Anokye-Danso render the invention unpatentable as claimed.
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Lim et al. (US 20160220613 A1, on IDS 11/04/2020, previously cited) in view of Lai et al. (Scientific Reports, 2017, on IDS 07/05/2022, previously cited), Mathieu et al. (Cell Stem Cell, 2015, previously cited) and Anokye-Danso et al. (Cell Stem Cell, 2011, previously cited), as applied to claim 1, and further in view of Collas et al. (Reproductive BioMedicine Online, 2006, previously cited).
In regards to claims 7, Lim as modified by Lai and Mathieu, does not explicitly teach that the de-differentiated fibroblasts were produced upon exposure to stem cells and/or cytoplasm from stem cells.
However, Collas teaches while functional reprogramming of differentiated cells (such as fibroblasts) to pluripotency may present beneficial applications in regenerative medicine, and while somatic cell nuclear transfer may offer this possibility, technical hurdles and ethical guidelines currently prevent application of this technology (Abstract, p762). Therefore, Collas teaches a method that includes the fusion of different cells with embryonic stem cells and the use of extract from pluripotent stem cells to reprogram differentiated cells into multipotent or pluripotent cells (Abstract, p762). Therefore, a person of ordinary skill in the arts would have been motivated to “de-differentiate” somatic cells such as fibroblast by exposure to pluripotent stem cells or cytoplasm from pluripotent stem cells because it would provide an alternative means of establishing pluripotent cells which can be used for therapeutic application while overcoming technical and ethical limitations of other methods. Furthermore, because Collas teaches method for utilizing stem cell extracts (Figure 1, p764) for reprogramming cells, and Lim, Lai, and Collas are all in the same technical field of utilizing MSCS for clinical purposes, it could have been done with predictable results and a reasonable expectation of success.
Therefore, the combined teachings of Lim, Lai, Mathieu, Anokye-Danso, and Collas render the invention unpatentable as claimed.
Claims 11-12 are rejected under 35 U.S.C. 103 as being unpatentable over Lim et al. (US 20160220613 A1, on IDS 11/04/2020, previously cited) in view of Lai et al. (Scientific Reports, 2017, on IDS 07/05/2022, previously cited), Mathieu et al. (Cell Stem Cell, 2015, previously cited) and Anokye-Danso et al. (Cell Stem Cell, 2011, previously cited), as applied to claim 1 above, and further in view of Jung et al. (ACS Chemical Biology, 2014, previously cited).
In regards to claims 11-12, Lim as modified by Lai and Mathieu, does not explicitly teach that the de-differentiated fibroblasts were produced upon exposure to one or more DNA methyltransferase inhibitors.
However, a person of ordinary skill in the arts would have been motivated to de-differentiate fibroblasts in conditions with a DNA methyltransferase inhibitor such as decitabine because Jung teaches that decitabine is a well-characterized DNA methyltransferase inhibitor, that can improve reprogramming efficiency; allow for reprogramming without the need for the factor c-Myc which is known to be oncogenic; and facilitate erasure of epigenetic memory and reduce DNA hypermethylation (DNA methyltransferases (DNMTs), p87). Furthermore, because Jung teaches that the use of decitabine is well characterized and points to methods for using decitabine to reprogram fibroblasts (DNA methyltransferases (DNMTs), p87), it could have been done with predictable results and a reasonable expectation of success.
Therefore, the combined teachings of Lim, Lai, Mathieu, Anokye-Danso, and Jung render the invention unpatentable as claimed.
Claim 29 is rejected under 35 U.S.C. 103 as being unpatentable over Lim et al. (US 20160220613 A1, on IDS 11/04/2020, previously cited) in view of Lai et al. (Scientific Reports, 2017, on IDS 07/05/2022, previously cited), Mathieu et al. (Cell Stem Cell, 2015, previously cited) and Anokye-Danso et al. (Cell Stem Cell, 2011, previously cited), as applied to claims 1 and 3 above, and further in view of Erwin et al. (WO2010088775A1, 2010) and Bach et al. (Oncotarget, 2017).
In regards to claim 3, Lim does not explicitly teach that the exosomes express the marker CD56 (which is the same as NCAM).
However, as taught by Erwin, notochordal conditioned media, comprises soluble factors secreted by NCAM (CD56)-positive notochordal cells cultured under hypoxic conditions (paragraphs [0038-0041, 00296]). Continuing, Erwin teaches that this media is useful for treating degenerative disc disease in patients (paragraph [0017]). As taught by Bach, extracellular vesicles (of which exosomes are a type) found in notochordal conditioned media exert regenerative effects on nucleus pulposus cells in the intervertebral disc (Abstract, p88845).
Therefore, a person of ordinary skill in the art would have been motivated to include CD56-positive exosomes because they would promote regeneration of nucleus pulposus cells in the intervertebral disc. Furthermore, because Erwin teaches that degenerative disc diseases may be treated with conditioned media comprising CD56/NCAM (claims 19, 43) and because Bach teaches that vesicles derived from notochordal conditioned media exert regenerative effects on nucleus pulposus cells in the intervertebral disc, it could have been done with predictable results and a reasonable expectation of success.
Therefore, the combined teachings of Lim, Lai, Mathieu, Anokye-Danso, Erwin, and Bach render the invention unpatentable as claimed.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-3, 5, 7, 10-1, 13-14, and 16 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of copending Application No. 18/736,046 in view of Cheng et al. (Journal of Cellular and Molecular Medicine, first published 08/14/2017, on IDS 07/05/2022, previously cited).
Although the claims at issue are not identical, they are not patently distinct from each other because both inventions are drawn to methods for treating disc degeneration in patients which requires a step of exposing fibroblasts to valproic acid and hypoxic conditions (0.1-20% which overlaps with at least 2%-8%) (thus, de-differentiating fibroblasts). Both inventions require steps of administering fibroblasts.
While copending Application No. 18/736,046 does not require a step of providing conditioned media comprising exosomes from the de-differentiated fibroblasts to a patient, a person of ordinary skill in the art would have been motivated to provide conditioned media comprising exosomes from the de-differentiated fibroblasts to a patient because Cheng specifically teaches that exosomes in conditioned media from MSCs (which can be “de-differentiated fibroblasts”, as discussed above) inhibit nucleus pulposus cell apoptosis and alleviate interverbal disc degeneration (Abstract, p261; Exosome characterization, Exosomes uptake by NPCs, p263). Cheng also teaches that these exosomes are CD63 positive (Exosome characterization, p263).
Furthermore, because Cheng teaches that patients could be effectively treated with MSC-exosomes, and that this reduced cell apoptosis and disc degeneration (Intradiscal injection of MSC-exosomes alleviated the NPC apoptosis and IVD degeneration in a rat model, p271), it could have been done with predictable results and a reasonable expectation of success. This is a provisional nonstatutory double patenting rejection.
Claim 12 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of copending Application No. 18/736,046 in view of Cheng et al. (Journal of Cellular and Molecular Medicine, first published 08/14/2017, on IDS 07/05/2022, previously cited), as applied to claims 1 and 11 above, and further in view of Jung et al. (ACS Chemical Biology, 2014, previously cited).
In regards to claim 12, while Copending Application No. 18/736,046 also teaches steps of exposing cells to a DNA methyl transferase inhibitor (claim 4) but is silent as to the specific inhibitor.
However, a person of ordinary skill in the arts would have been motivated to de-differentiate fibroblasts in conditions with a DNA methyltransferase inhibitor such as decitabine because Jung teaches that decitabine is a well-characterized DNA methyltransferase inhibitor, that can improve reprogramming efficiency; allow for reprogramming without the need for the factor c-Myc which is known to be oncogenic; and facilitate erasure of epigenetic memory and reduce DNA hypermethylation (DNA methyltransferases (DNMTs), p87). Furthermore, because Jung teaches that the use of decitabine is well characterized and points to methods for using decitabine to reprogram fibroblasts (DNA methyltransferases (DNMTs), p87), it could have been done with predictable results and a reasonable expectation of success.
Claim 15 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of copending Application No. 18/736,046 in view of Cheng et al. (Journal of Cellular and Molecular Medicine, first published 08/14/2017, on IDS 07/05/2022, previously cited), as applied to claims 1 and 14 above, and further in view of Lim et al. (US 20160220613 A1, on IDS 11/04/2020, previously cited).
In regards to claim 15, while Copending Application No. 18/736,046 does not explicitly teach a step of isolating exosomes by anion exchange chromatography, it would have been predictably obvious to use this technique because Lim teaches that the exosomes may be purified by ion (of which an anion is a type) exchange chromatography (paragraph [0284]).
Claim 29 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of copending Application No. 18/736,046 in view of Cheng et al. (Journal of Cellular and Molecular Medicine, first published 08/14/2017, on IDS 07/05/2022, previously cited), as applied to claims 1 and 3 above, and further in view of Erwin et al. (WO2010088775A1, 2010) and Bach et al. (Oncotarget, 2017).
In regards to claim 29, while Copending Application No. 18/736,046 does not explicitly require exosomes that express the marker CD56, as taught by Erwin, notochordal conditioned media, comprises soluble factors secreted by NCAM (CD56)-positive notochordal cells cultured under hypoxic conditions (paragraphs [0038-0041, 00296]). Continuing, Erwin teaches that this media is useful for treating degenerative disc disease in patients (paragraph [0017]). As taught by Bach, extracellular vesicles (of which exosomes are a type) found in notochordal conditioned media exert regenerative effects on nucleus pulposus cells in the intervertebral disc (Abstract, p88845).
Therefore, a person of ordinary skill in the art would have been motivated to include CD56-positive exosomes because they would promote regeneration of nucleus pulposus cells in the intervertebral disc. Furthermore, because Erwin teaches that degenerative disc diseases may be treated with conditioned media comprising CD56/NCAM (claims 19, 43) and because Bach teaches that vesicles derived from notochordal conditioned media exert regenerative effects on nucleus pulposus cells in the intervertebral disc, it could have been done with predictable results and a reasonable expectation of success.
Response to Arguments
Applicant argues that the specification teaches that de-differentiated fibroblasts exposed to the synergistic combination as in claim 1 provides better inhibition of TNF-alpha induced apoptosis and inhibition of stimulated NP cell proliferation than exosomes from undifferentiated fibroblasts and exosomes from fetal calf serum (citing Figs. 1 and 2; Remarks, p4).
Applicant's arguments filed 11/14/2025 have been fully considered but they are not persuasive.
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., synergistic effects) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Additionally, in as much as Applicant alleges unexpected results, whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980) (see MPEP 716.02(d)). As above, the claims do require synergistic effects.
Applicant argues that the cells as taught by Lai are not MSCs, but rather specifically MSC-like and are distinguishable from MSC (citing Fig. 2 of Lai; Remarks, p5).
Applicant's arguments filed 11/14/2025 have been fully considered but they are not persuasive.
Lai explicitly states that the resultant cells are “induced mesenchymal stem cells” (Abstract, p1), which are a type of MSC. Furthermore, Lai also teaches that “iMSCs express all traditional MSC markers” (p2). In regards to the term “MSC-like” a person of ordinary skill in the art would have understood that Lai uses the term because these cells are reprogrammed from fibroblasts and not primary MSCs.
Applicant argues that it would not be obvious to expose fibroblasts to both valproic and hypoxia as amended in claim 1 (Remarks, p4-7).
Applicant's arguments filed 11/14/2025 have been fully considered but they are not persuasive.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
As discussed above, while Lim as modified by Lai is silent as to the oxygen conditions of the de-differentiating cells, a person of ordinary skill in the arts would have been motivated to de-differentiate fibroblasts in hypoxic conditions because Mathieu teaches that pluripotent stem cells (OCT-4 expressing cells) have distinct metabolic requirements, and reprogramming cells to pluripotency requires a shift from oxidative to glycolytic metabolism (Summary, p592). Moreover, in particular, Mathieu teaches that reprogramming is significantly more efficient under hypoxic (2% and 5%, which lies within the ranges as in claim 13) conditions (Reprogramming process has hypoxic expression signature, p593). Furthermore, because Mathieu teaches methods for reprogramming fibroblasts under hypoxic (2% and 5%) conditions (Reprogramming process has hypoxic expression signature, p593; Cell culture and reprogramming, p602); and Lim, Lai, and Mathieu are in the same technical field of utilizing OCT-4 positive cells, it could have been done with predictable results and a reasonable expectation of success.
Additionally, as discussed above, Lim as modified by Lau and Mathieu does not explicitly teach a step of de-differentiating fibroblasts by exposure to valproic acid (VPA), a person of ordinary skill in the arts would have been motivated to de-differentiate fibroblasts with VPA because Anokye-Danso teaches that VPA is required for reprogramming fibroblasts by specifically degrading Hdac2 which allows for highly efficient reprogramming without expression of other known reprogramming factors (Introduction, p376). Furthermore, because Anokye-Danso teaches method for reprogramming fibroblasts with VPA (Figure 1, p377), and Lai, Lim, Mathieu, and Anokye-Danso are in the same technical field of utilizing OCT-4 positive cells, it could have been done with predictable results and a reasonable expectation of success.
Applicant argues that the conditioned media comprising exosomes from different types of dedifferentiated cells with differ in content and functionality, even if they all express OCT-4 (citing Fig. 3 of Valencia et al., Cancers, 2021, on IDS 11/14/2025). Continuing, Applicant argues that considering that diverse types of cells express OCT-4, one of skill in the art would not expect OCT-expressing cells to have the same content and functionality (Remarks, p5-6).
Applicant's arguments filed 11/14/2025 have been fully considered but they are not persuasive.
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., specific types of cells or specific content/functionality) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
In particular, the claims are generically drawn to “de-differentiated fibroblasts”, which as discussed above, are broadly interpreted to refer to any fibroblast-derived cell that has reverted to a more generalized or primitive condition, including any fibroblast-derived cell that expresses OCT-4.
Moreover, the claims do not require that these cells have any specific functionality other their resultant conditioned media being capable of being administered to an individual. However, as discussed above, Lim teaches that the exosomes may be contained within a composition that may be conditioned media that may be used as a therapy (paragraphs [0173-0177, and 0282]).
In regards to the double patenting rejection over copending Application No. 18/736,046 in view of Chen, Applicant argues that the current claims are directed to culturing fibroblasts with one or more HDAC inhibitors and exposure to hypoxia. Applicant argues that the limitation of hypoxic conditions is not prima facie obvious over the Application No. 18/736,046 in view of Chen or copending Application No. 17/251,587 in view of Chen (Remarks, p7-8).
Applicant's arguments filed 11/14/2025 have been fully considered but they are not persuasive.
Although the claims at issue are not identical, they are not patently distinct from each other because both inventions are drawn to methods for treating disc degeneration in patients which have been dedifferentiated by exposing fibroblasts to valproic acid and hypoxic conditions (0.1-20% which overlaps with the hypoxic conditions of least 2%-8%).
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOSEPH (PAUL) MIANO whose telephone number is (571)272-0341. The examiner can normally be reached Mon-Fri from 8:30am to 5:30pm.
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/JOSEPH PAUL MIANO/Examiner, Art Unit 1631